Sudden death during the first year of life is a leading cause of infant mortality in developed countries. Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy as well as to perinatal and neonatal morbidity and mortality, but the relationship to genetic disorders presenting later in life is unclear. For exampe, mutations in SCN5A encoding the cardiac sodium channel have been associated with a spectrum of increased sudden death risk extending from fetal life to adulthood. Carriers of certain SCN5A mutations present with earlier onset and more severe congenital arrhythmia syndromes, but the molecular basis for the unexpected severity and lethality of certain variants during early life is unknown. This is the first competing renewal for our research study that investigates links between sudden death in early life and cardiac ion channelopathies. The overarching goal of our new proposal is to understand the molecular genetic basis for arrhythmia susceptibility during early development and to determine the clinical value of this knowledge. In Specific Aim 1, we will elucidate the contribution of developmentally regulated alternative splicing of SCN5A to arrhythmia susceptibility in early life. These experiments are based upon our preliminary evidence that a specific splice variant of SCN5A is expressed more prominently in fetal and infant heart than adult heart, which prompted our hypothesis that certain mutations and rare genetic variants cause greater functional disturbances in channels encoded by the alternatively spliced transcript. In Specific Aim 2, we will determine correlations between a prolonged QTc observed during the neonatal period, LQTS gene mutations and persistent LQTS in later life. This work involves a strategic partnership between the Principal Investigator and investigators in Italy who will provide access to a large and unique cohort of infants and children incidentally found to have prolonged QTc intervals by systematic ECG screening. Finally in Specific Aim 3, we will determine the spectrum of genetic variation associated with malignant perinatal ventricular arrhythmia syndromes by performing exome sequencing of a cohort of subjects with unusually severe or malignant cardiac arrhythmias documented during early life. The unifying hypothesis underlying the proposed experiments is that sudden death during a period extending from mid- gestation through 1 year of life can be associated with mutations in arrhythmia susceptibility genes, and that factors such as developmentally regulated SCN5A alternative splicing or mutations with unusually severe functional consequences, possibly in novel genes, potentiate the risk of life-threatening events. PUBLIC HEALTH RELEVANCE: Sudden unexplained death during the first year of life is a major reason for infant mortality in the Western world. Congenital long-QT syndrome, a genetic condition associated with life-threatening disturbances in heart rhythm, can increase risk of sudden death during infancy, in newborns and even in the unborn. Our study seeks to determine the molecular basis for unusually severe forms of long-QT syndrome, to understand the long-term clinical significance of incidentally discovered long-QT syndrome in neonates, and to discover new genetic causes of life-threatening arrhythmia syndromes in babies.